Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Having -c- – wherein x is chalcogen – bonded directly to...
Reexamination Certificate
1998-08-26
2001-03-06
Aulakh, Charanjit S. (Department: 1612)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Having -c-, wherein x is chalcogen, bonded directly to...
C546S221000, C546S216000, C546S213000, C546S205000, C546S194000, C546S188000, C544S129000, C514S326000, C514S319000, C514S318000, C514S316000, C514S235500
Reexamination Certificate
active
06197791
ABSTRACT:
BACKGROUND OF THE INVENTION
Matrix metalloproteinases (MMPs) are a group of enzymes that have been implicated in the pathological destruction of connective tissue and basement membranes. These zinc containing endopeptidases consist of several subsets of enzymes including collagenases, stromelysins and gelatinases. Of these classes, the gelatinases have been shown to be the MMPs most intimately involved with the growth and spread of tumors. It is known that the level of expression of gelatinase is elevated in malignancies, and that gelatinase can degrade the basement membrane which leads to tumor metastasis. Angiogenesis, required for the growth of solid tumors, has also recently been shown to have a gelatinase component to its pathology. Furtherrnore, there is evidence to suggest that gelatinase is involved in plaque rupture associated with atherosclerosis. Other conditions mediated by MMPs are restenosis, MMP-mediated osteopenias, inflammatory diseases of the central nervous system, skin aging, tumor growth, osteoarthritis, rheumatoid arthritis, septic arthritis, corneal ulceration, abnormal wound healing, bone disease, proteinuria, aneurysmal aortic disease, degenerative cartilage loss following traumatic joint injury, demyelinating diseases of the nervous system, cirrhosis of the liver, glomerular disease of the kidney, premature rupture of fetal membranes, inflammatory bowel disease, periodontal disease, age related macular degeneration, diabetic retinopathy, proliferative vitreoretinopathy, retinopathy of prematurity, ocular inflammation, keratoconus, Sjogren's syndrome, myopia, ocular tumors, ocular angiogenesis
eo-vascularization and corneal graft rejection. For recent reviews, see: (1) Recent Advances in Matrix Metalloproteinase Inhibitor Research, R. P. Beckett, A. H. Davidson, A. H. Drummond, P. Huxley and M. Whittaker, Research Focus, Vol. 1, 16-26, (1996), (2) Curr. Opin. Ther. Patents (1994) 4(1): 7-16, (3) Curr. Medicinal Chem. (1995) 2: 743-762, (4) Exp. Opin. Ther. Patents (1995) 5(2): 1087-110, (5) Exp. Opin. Ther. Patents (1995) 5(12): 1287-1196.
TNF-&agr; converting enzyme (TACE) catalyzes the formation of TNF-&agr; from membrane bound TNF-&agr; precursor protein. TNF-&agr; is a pro-inflammatory cytokine that is now thought to have a role in rheumatoid arthritis, septic shock, graft rejection, cachexia, anorexia, inflammation, congestive heart failure, inflammatory disease of the central nervous system, inflammatory bowel disease, insulin resistance and HIV infection in addition to its well documented antitumor properties. For example, research with anti- TNF-&agr; antibodies and transgenic animals has demonstrated that blocking the formation of TNF-&agr; inhibits the progression of arthritis. This observation has recently been extended to humans as well.
It is expected that small molecule inhibitors of MMPs and TACE therefore have the potential for treating a variety of disease states. While a variety of MMP and TACE inhibitors have been identified and disclosed in the literature, the vast majority of these molecules are peptidic and peptide-like compounds that one would expect to have bioavailability and pharmacokinetic problems common to such compounds that would limit their clinical effectiveness. Low molecular weight, potent, long acting, orally bioavailable inhibitors of MMPs and/or TACE are therefore highly desirable for the potential chronic treatment of the above mentioned disease states.
Recently, two references have appeared (U.S. Pat. No. 5,455,258 and European Patent Appl. 606,046) that disclose arylsulfonamido-substituted hydroxyamic acids. These documents cover compounds exemplified by CGS 27023A. These are the only non-peptide matrix metalloproteinase inhibitors disclosed to date.
Salah et al., Liebigs Ann. Chem. 195, (1973) discloses some aryl substituted thio and aryl substituted sulfonyl acetohydroxamic acid derivatives of general formula 1. These compounds were prepared to study the Mannich reaction. Subsequently, they were tested for their fungicidal activity.
Some sulfone carboxylic acids are disclosed in U.S. Pat. No. 4,933,367. Those compounds were shown to exhibit hypoglycemic activity.
SUMMARY OF THE INVENTION:
The present invention relates to novel, low molecular weight, non-peptide inhibitors of matrix metalloproteinases (MMPs) and TNF-&agr; converting enzyme (TACE) for the treatment of arthritis, tumor metastasis, tissue ulceration, abnormal wound healing, periodontal disease, bone disease, diabetes (insulin resistance) and HIV infection.
In accordance with this invention there is provided a group of compounds of general formula I
wherein:
R
1
is alkyl of 1 to 18 carbon atoms, optionally substituted with one or two groups selected independently from R
5
;
alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R
5
;
alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R
5
;
aryl of 6 to 10 carbon atoms, optionally substituted with one or two groups selected independently from R
5
;
cycloalkyl of 3 to 8 carbon atoms, optionally substituted with one or two groups selected independently from R
5
;
saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR
7
, optionally substituted with one or two groups selected independently from R
5
;
or heteroaryl-(CH
2
)
0−6
— wherein the heteroaryl group is 5 to 6 membered with one or two heteroatoms selected independently from O, S, and N and may be optionally substituted with one or two groups selected independently from R
5
;
A is —S—, —SO— or SO
2
—;
R
2
and R
3
, taken with the carbon atom to which they are attached, form a 5 to 7 membered heterocyclic ring containing O, S or N—R
7
optionally having one or two double bonds;
R
4
is hydrogen,
alkyl of 1 to 6 carbon atoms, optionally substituted with one or two groups selected independently from R
5
;
alkenyl of 3 to 18 carbon atoms having 1 to 3 double bonds, optionally substituted with one or two groups selected independently from R
5
;
alkynyl of 3 to 18 carbon atoms having 1 to 3 triple bonds, optionally substituted with one or two groups selected independently from R
5
;
phenyl or naphthyl optionally substituted with one or two groups selected independently from R
5
;
C
3
to C
8
cycloalkyl or bicycloalkyl optionally substituted with one or two groups selected independently from R
5
;
saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR
7
, optionally substituted with one or two groups selected independently from R
5
;
R
5
is H, C
7
-C
11
aroyl, C
2
-C
6
alkanoyl, C
1
to C
12
alkyl, C
2
to C
12
alkenyl, C
2
-C
12
alkynyl, F, Cl, Br, I, CN, CHO, C
1
-C
6
alkoxy, aryloxy, heteroaryloxy, C
3
-C
6
alkenyloxy, C
3
-C
6
alkynyloxy, C
1
-C
6
alkoxyaryl, C
1
-C
6
alkoxyheteroaryl, C
1
-C
6
alkylamino-C
1
-C
6
alkoxy, C
1
-C
2
alkylene dioxy, aryloxy-C
1
-C
6
alkyl amine, C
1
-C
12
perfluoro alkyl, S(O)
n
—C
1
-C
6
alkyl, S(O)
n
-aryl where n is 0, 1 or 2; OCOO C
1
-C
6
alkyl, OCOOaryl, OCONR
6
, COOH, COO C
1
-C
6
alkyl, COOaryl, CONR
6
R
6
, CONHOH, NR
6
R
6
, SO
2
NR
6
R
6
, NR
6
SO
2
aryl, —NR
6
CONR
6
R
6
, NHSO
2
CF
3
, SO
2
NHheteroaryl,SO
2
NHCOaryl, CONHSO
2
—C
1
-C
6
alkyl, CONHSO
2
aryl, SO
2
NHCOaryl, CONHSO
2
—C
1
-C
6
alkyl, CONHSO
2
aryl, NH
2
, OH, aryl, heteroaryl, C
3
to C
8
cycloalkyl; or saturated or unsaturated 5 to 10 membered mono or bicyclic heterocycle containing one heteroatom selected from O, S or NR
7
, wherein C
1
-C
6
alkyl is straight or branched, heteroaryl is a 5-10 membered mono or bicyclic heteroaryl group having 1 to 3 heteroatoms selected independently from O, S or NR
7
and aryl is phenyl or naphthyl, optionally substituted by 1 or 2 groups selected from halogen, cyano, amino, nitro, C
1
-C
6
alkyl, C
1
-C
6
alkoxy, or hydroxy;
R
6
is H, C
1
to C
18
alkyl optionally subst
Baker Jannie Lea
Davis Jamie Marie
Grosu George Theodore
Levin Jeremy Ian
Venkatesan Aranapakam Mudumbai
American Cyanamid Company
Aulakh Charanjit S.
Barrett Rebecca R.
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